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(DAT) for Suspected Diphtheria Cases Expanded Access Investigational New Drug (IND) Application Protocol: Use of Diphtheria Antitoxin (DAT) for Suspected Diphtheria Cases BB-IND 11184 Protocol CDC IRB # 4167 Version Number 8.0 March 9, 2020 IND Sponsored by Centers for Disease Control and Prevention (CDC) This expanded access IND protocol for DAT from the CDC contains information intended to guide treating clinicians regarding the use of investigational DAT and should only be used for the stated purpose and scope of the IND protocol in accordance with the applicable IND regulatory requirements. This document, and the contents within the document, should not be altered or reproduced without prior authorization from the CDC. PROGRAM CONTACT INFORMATION Principal Investigator: Anna M. Acosta, MD Meningitis and Vaccine-Preventable Diseases Branch Division of Bacterial Diseases National Center for Immunization and Respiratory Diseases Centers for Disease Control and Prevention 1600 Clifton Road NE, Mailstop H24-6 Atlanta, GA 30329 Office: (404) 639-1951; Fax: (404) 679-5072 E-mail: [email protected] Regulatory Affairs: CAPT Yon Yu, Pharm.D. Regulatory Affairs and Clinical Guidelines Team Lead Division of Preparedness and Emerging Infections National Center for Emerging and Zoonotic Infectious Diseases Centers for Disease Control and Prevention 1600 Clifton Road NE, Mailstop H24-11 Atlanta, GA 30329 Office: (404) 639-3046 E-mail: [email protected] BB-IND 11184 Diphtheria Antitoxin (DAT) Protocol CDC IRB #4167 Version 8.0 Page 1 March 9, 2020 TABLE OF CONTENTS Page 1.0 OBJECTIVE ......................................................................................................................................... 3 2.0 BACKGROUND .................................................................................................................................. 3 3.0 PRODUCT INFORMATION ............................................................................................................... 4 IND PROGRAM DESCRIPTION ........................................................................................................ 5 4.0 PATIENT ELIGIBILITY FOR DAT ................................................................................................... 5 5.0 5.1 Therapeutic Use .......................................................................................................................... 5 5.2 Prophylactic Use ......................................................................................................................... 6 6.0 DAT TREATMENT PROCEDURES .................................................................................................. 7 6.1 Informed Consent/Parental Permission ....................................................................................... 7 6.2 Precautionary measures............................................................................................................... 8 6.3 Tests for Sensitivity to DAT ....................................................................................................... 8 6.4 Desensitization ............................................................................................................................ 9 6.5 DAT Administration ................................................................................................................. 10 6.6 Possible adverse reactions following administration of DAT ................................................... 11 7.0 REQUIRED PATIENT MONITORING AND REPORTING OF ADVERSE EVENTS ................. 12 7.1 Patient Monitoring .................................................................................................................... 12 7.2 Definitions of Adverse Events (21 CFR 312.32) ...................................................................... 12 7.3 Recording and Reporting Adverse Events ................................................................................ 13 8.0 LABORATORY TESTING ............................................................................................................... 14 9.0 OPTIONAL BLOOD DRAWS .......................................................................................................... 14 10.0 LOCAL AND STATE HEALTH DEPARTMENT NOTIFICATION .............................................. 15 11.0 DATA COLLECTION AND STORAGE .......................................................................................... 15 12.0 REFERENCES ................................................................................................................................... 18 Appendix 1: Informed Consent/Parental Permission Form for Use of DAT for Suspected Diphtheria Cases Appendix 2: Diphtheria Antitoxin Treatment and Adverse Effects Form Appendix 3: CDC Diphtheria Worksheet Appendix 4: Information for Close Contacts Appendix 5: Form FDA 1572 (Statement of the Investigator) Appendix 6: Investigational Product Accountability and Disposition Form Appendix 7: A copy of CDC IRB’s Approval Letter Appendix 8: Optional Additional Blood Draws: Instructions for Processing Serum Samples for MassBiologics • Appendix 8A: Informed Consent/Parental Permission Form for Additional Blood Draws With the Use of DAT for Suspected Diphtheria Cases • Appendix 8B: Assent for Additional Blood Draws with the use of DAT for Suspected Diphtheria cases aged 12-17 years old • Appendix 8C: Assent for Additional Blood Draws with the use of DAT for Suspected Diphtheria cases aged 7-11 years old BB-IND 11184 Diphtheria Antitoxin (DAT) Protocol CDC IRB #4167 Version 8.0 Page 2 March 9, 2020 OBJECTIVE The purpose of this Investigational New Drug (IND) protocol is to provide access to investigational diphtheria antitoxin (DAT) for treatment of suspected diphtheria cases, and for prophylactic use under exceptional circumstances in an exposed contact, in the absence of Food and Drug Administration (FDA)- approved drugs for treatment or prophylaxis of diphtheria. BACKGROUND Diphtheria is a clinical syndrome caused by an exotoxin produced by the bacterium Corynebacterium diphtheriae; non-toxin-producing strains of C. diphtheriae are not associated with the syndrome but can cause localized inflammation. Most commonly, toxigenic infection results in respiratory or cutaneous disease. Diphtheria is transmitted from person to person by respiratory droplets or contact with discharges from skin lesions. The severe local and systemic manifestations of respiratory diphtheria result after diphtheria toxin binds to a wide range of cells, including epithelial, nerve and muscle cells. The toxin interferes with enzymes necessary for protein synthesis, leading to cell damage and death. Local effects include severe inflammation and pseudomembrane (a firmly-adherent leather-like exudate that looks like a membrane) formation in the nose, and/or pharynx and/or larynx, which can progress to life-threatening airway obstruction. Systemic effects may occur from absorption of diphtheria toxin and include myocarditis, polyneuritis, and, rarely, renal failure. There are four biotypes of C. diphtheriae: gravis, mitis, belfanti and intermedius. All four biotypes are capable of producing an identical exotoxin. No difference in pathogenicity has been demonstrated among the four biotypes. Some strains of Corynebacterium ulcerans can also produce an identical diphtheria toxin. A respiratory diphtheria-like illness can result from an infection caused by toxin-producing strains of C. ulcerans.1 The onset of disease is insidious. Following an incubation period of 1-5 days, low-grade fever begins and a pharyngeal pseudomembrane develops over 2-3 days, along with lymphadenopathy and diffuse systemic toxicity, resulting in a rapid, thready pulse, weakness, and irritability. Although the systemic effects of diphtheria can occur in the first week of illness, they usually occur later (1-2 weeks after onset for myocarditis, 2-8 weeks for neuritis). The hallmark of suspected respiratory diphtheria is a low-grade febrile, membranous pharyngitis of insidious onset. In a minority of instances, respiratory diphtheria can result from an isolated diphtherial infection in the larynx or nasal lining. Other diseases that can occasionally produce a similar membranous pharyngitis include streptococcal pharyngitis and infectious mononucleosis. Patients who have been treated with immunosuppressive drugs can present with a membrane that mimics diphtheria. Isolated diphtherial laryngitis can usually be differentiated from Haemophilus influenzae type b epiglottitis, spasmodic croup, or the presence of a foreign body by the gradual onset of diphtherial disease. Differentiation of isolated diphtherial laryngitis from viral laryngotracheitis or bacterial tracheitis can be difficult on the basis of symptoms alone. DAT was first produced in the 1890s and is still being produced using serum from horses that are hyperimmunized with diphtheria toxoid. The evidence for efficacy of equine-based DAT for the treatment of respiratory diphtheria is based on observations and studies done several decades ago. Mortality rates for clinical diphtheria frequently exceeded 50% in the pre-antitoxin era. Almost as soon as antitoxin was available, clinical experience showed dramatic declines in mortality in groups of patients treated with antitoxin compared to historical control groups or groups treated at hospitals not using antitoxin. In one controlled trial in which patients at a hospital were allocated to antitoxin treatment or no antitoxin treatment on an alternating day schedule,
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